Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8) is a newly described oncogenic herpesvirus originally identified in acquired immunodeficiency syndrome (AIDS)-associated Kaposi's sarcoma (KS) lesions (Chang et al., Science 266:1865, 1994). KSHV sequences are regularly detected in KS lesions from human immunodeficiency virus (HIV)-infected and non-infected individuals, primary effusion lymphoma (PEL), and a proportion of cases of Castleman's disease (Neipel et al., J Virol 71:4187, 1997; Schulz, J Gen Virol 79:1573, 1998). KSHV encodes various proteins that have features suggesting their role in promoting cellular growth and transformation, including viral homologues of cyclin D, G-protein coupled receptor, interferon regulatory factor, macrophage inflammatory proteins and IL-6. All these viral proteins display structural similarities to their cellular counterparts. KSHV viral IL-6 (vIL-6), encoded at open reading frame K2, has 24.8% amino acid sequence identity (49.7% similarity) to human IL-6 (hIL-6) and 24.2% identity (47.9% similarity) to murine IL-6 (mIL-6) (Moore et al., Science 274:1739, 1996; Neipel, et al., J Virol 71:839, 1997; Nicholas et al., Nat Med 3:287, 1997).
Cellular IL-6 acts on a wide variety of cell types, serving as a growth factor for myeloma, plasmacytoma and B cells, and promoting the terminal differentiation of B cells into Ig-secreting cells (Kishimoto et al., Blood 86:1243, 1995; Peters, et al., Blood 92:3495, 1998). This cytokine has been implicated in the pathogenesis of several diseases, including multiple myeloma and rheumatoid arthritis as well as KSHV-related diseases (Neipel et al., J Virol 71:4187, 1997). The IL-6 family of cytokines exerts its activities via receptor complexes that contain at least one subunit of the signal transducing protein gp130. The members of this family, which include IL-6 LIF, IL-11, oncostatin M (OSM), ciliary neurotrophic factor and cardiotrophin-1, are structurally related and exert many overlapping biological activities (Kishimoto et al., Blood 86:1243, 1995; Peters et al., Blood 92:3495, 1998). Cell stimulation by any member of the IL-6 family of cytokines triggers homo- or hetero-dimerization of gp130. The dimerization of gp130 leads to activation of associated cytoplasmic tyrosine kinases and subsequent modification of transcription factors (Taga et al., Annu Rev Immunol 15:797, 1997). In addition to gp30, the high affinity, signaling receptor complexes for the IL-6-type cytokines contain at least one other receptor subunit. IL-6 utilizes a specific α-subunit (IL-6Rα), and the high affinity receptor-ligand complex consists of two molecules of each gp130, IL-6 and IL-6Rα (Hammacher et al., J. Biol Chem 273:22701, 1998). The formation of such hexameric receptor-complexes occurs in all situations in which the ligand requires a nonsignaling receptor for its association with gp130.
In spite of its limited sequence homology, vIL-6 displays many biological functions of cellular IL-6 (Aoki et al., Blood 93:4034, 1999). Studies in vitro and in vivo have shown that vIL-6 can stimulate the growth of KSHV-infected PEL cells (Jones et al., Blood 94:2871, 1999), promote hematopoiesis, act as an angiogenic factor by inducing vascular endothelial growth factor (Aoki et al., Blood 93:4034, 1999), and activate STAT1, STAT3 and JAK1 phosphorylation (Molden et al., J Biol Chem 272:19625, 1997). The interactions of vIL-6 with the IL-6 receptor chains gp130/IL-6Rα have been studied both in human and murine cell culture systems (Nicholas et al., Nat Med 3:287, 1997; Molden, J Biol Chem 272:19625, 1997; Burger et al., Blood 91:1858, 1998; Wan et al., J Virol 73:8268, 1999; Gage et al., AIDS 13:1851, 1999), but vIL-6 directed molecules that selectively interfere with this interaction have yet to be developed.